WO2007119588A1 - Brain function-improving agent, and functional food containing the improving agent - Google Patents

Brain function-improving agent, and functional food containing the improving agent Download PDF

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Publication number
WO2007119588A1
WO2007119588A1 PCT/JP2007/056869 JP2007056869W WO2007119588A1 WO 2007119588 A1 WO2007119588 A1 WO 2007119588A1 JP 2007056869 W JP2007056869 W JP 2007056869W WO 2007119588 A1 WO2007119588 A1 WO 2007119588A1
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Prior art keywords
improving agent
brain function
functional food
food containing
group
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PCT/JP2007/056869
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French (fr)
Japanese (ja)
Inventor
Kazutoshi Kikkawa
Masahiko Nakano
Shiro Urano
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Mitsubishi Gas Chemical Company, Inc.
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Publication date
Application filed by Mitsubishi Gas Chemical Company, Inc. filed Critical Mitsubishi Gas Chemical Company, Inc.
Priority to US12/226,222 priority Critical patent/US20090192312A1/en
Priority to CA002649315A priority patent/CA2649315A1/en
Priority to EP07740307A priority patent/EP2011498A4/en
Priority to JP2007534943A priority patent/JPWO2007119588A1/en
Publication of WO2007119588A1 publication Critical patent/WO2007119588A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention comprises at least a brain function ameliorating agent characterized by containing as an active ingredient a pyroguchi quinoline quinone compound or a salt thereof represented by the general formula (1), and a functionality containing the improving agent.
  • a brain function improving agent containing coenzyme Q10 as an active ingredient together with the pyroguchi quinoline quinones or salts thereof represented by the general formula (1) and a functional food containing the improving agent.
  • the brain function improving agents and functional foods that are profitable have the effect of improving the learning-memory ability, and are therefore very useful in improving the brain function deterioration caused by the cause of vascular or organic disorders. is there.
  • R 1, R 2, and R are the same or different and represent a hydrogen atom, an alkyl group, an alkyl group,
  • Alzheimer's disease cerebrovascular disorders caused by cerebral infarction and cerebral hemorrhage, brain tumors, head trauma, infectious diseases, metabolic diseases, and the like.
  • the number of patients has increased significantly with the advancement of age. Alzheimer's disease is said to account for about 30% of dementia patients in Japan and 40-60% in the United States.It is characterized by a sudden short-term memory loss and personality disorder. Costs and nursing care have become major social issues.
  • acetylcholine a neurotransmitter
  • acetylcholine a neurotransmitter
  • senile plaques and neurofibrillary tangles present in the cerebral cortex and hippocampus
  • amyloid ⁇ 8 protein present in the center of senile plaques and tau
  • acetylcholinesterase inhibitors and the like have been developed. However, it is still difficult to say that they are effective enough! In other words, recovery after the onset of disease is usually difficult, and the current situation is that it must be treated symptomatically to slow the progression.
  • Patent Document 1 Japanese Patent Laid-Open No. 7-17855
  • Patent Document 2 JP-A-7-143862
  • Patent Document 3 Japanese Patent No. 3195594
  • An object of the present invention is to provide a preparation having an effect of improving brain function impaired by a vascular or non-vascular cause, and a functional food containing such a preparation.
  • the present invention comprises a brain-opened quinoline quinone or a salt thereof shown in the following 1 to 4 and a coenzyme Q10 as desired, and the brain function improving effect such as improvement of learning and memory ability reduction Specific to pharmaceuticals and functional foods that have
  • the present invention relates to a brain function improving agent that improves a decrease in learning and memory ability due to dementia such as Alzheimer's disease and Alzheimer's disease, and a functional food containing the improving agent.
  • a brain function improving agent characterized by comprising at least a pyroguchi quinoline quinone or a salt thereof represented by the general formula (1).
  • R 1, R 2, and R are the same or different and represent a hydrogen atom, an alkyl group, an alkyl group,
  • the brain function improving agent according to 1 or 2 above which is used to improve learning and memory ability.
  • the invention's effect is to any one of 1 to 3 above.
  • the present invention comprises a pyroguchi quinoline quinone or a salt thereof, or a pyro mouth quinoline quinone or a salt thereof and coenzyme Q10 as active ingredients, and has an effect of improving brain function such as learning 'improvement of decreased memory ability
  • the present invention relates to a brain function improving agent and a functional food containing the function improving agent.
  • the brain function improving agent for improving deterioration of learning / memory ability due to aging and dementia such as Alzheimer's disease and the like It relates to functional foods containing improvers.
  • the present invention relates to a brain function-improving agent containing pyroguchi quinoline quinones or a salt thereof, or pyro mouth quinoline quinones or a salt thereof and Coenzyme Q10 as active ingredients, and a functional food containing the improving agent.
  • Pillow mouth quinoline quinone was found in 1979 as a coenzyme for methanol-dehydrating enzymes of methanol-utilizing bacteria.
  • soybeans, soya beans, peppers, potatoes, parsley, potatoes It has also been detected in edible plants such as lotus roots and processed foods such as vinegar, tea, cocoa, natto and tofu.
  • Pyromouth quinoline quinones or salts thereof are produced by organic chemical synthesis methods (for example, JACS, No. 103, pages 5599-5600 (1981)) and fermentation methods (for example, JP-A No. 1-218597). It is possible.
  • pyroguchi quinoline quinones or salts thereof pyroguchi quinolines represented by the general formula (1) or salts thereof, alkaline metal salts such as sodium salts and potassium salts, alkaline earths such as magnesium salts and calcium salts
  • the salt is not limited to these.
  • pyro-quinoline quinones or salts thereof have been evaluated by intravenous injection or intraperitoneal injection for the purpose of pharmaceuticals, but administration by these routes is not practical and has side effects. There was a big problem that it was easy to come out. For this reason, the effect could not be exerted without causing side effects, and the effectiveness was not accurately evaluated, but the present inventors unexpectedly took the compound by taking it orally. We found that brain intake was effective at improving brain function such as learning and memory ability improvement at extremely low intakes, and that no side effects appeared even at high intakes where the range of effective intake was extremely wide. These facts indicate that pyrroloquinoline quinones or salts thereof can be used as a safe functional food material.
  • the pyroguchi quinoline quinones or salts thereof represented by the general formula (1) are used alone or in combination with Coenzyme Q10, but can also be used in combination with other functional food materials.
  • Functional food materials that can be combined include L-carcin, a- lipoic acid, vitamin B group, vitamin C, vitamin E, vitamins used as food, amino acids, austaxanthin, a — Carotenoids, carotenoids such as / 3-carotene, omega 3 fatty acids such as docosahexaenoic acid and eicosapentaenoic acid, omega 6 fatty acids such as arachidonic acid, etc. are not limited to these.
  • the cerebral quinoline quinones or salts thereof represented by the general formula (1) of the present invention or a brain function improving agent containing both of them and Coenzyme Q10 are in the form of food and drink, that is, drinks, syrups, various kinds. Even in the form of hospital food, nutrition-enhanced food, food and drink to eat everyday, tablets and capsules It can also be used in the form of agents and granules.
  • Additives used in the preparation include saccharides such as water, fructose and glucose, oils such as falling raw oil, soybean oil and olive oil, and glycols such as polyethylene glycol and polypropylene glycol. Can be used.
  • examples of the butyl alcohol, cellulose, gelatin, and surfactant include fatty acid esters, and examples of the plasticizer include glycerin, but are not limited thereto.
  • mice Male Wistar rats (9 weeks old) were used to feed PQQ '2Na 0.02% or CoQIO 0.3%, both in combination or singly, or in an additive-free diet. From the age of 12 weeks, using the Morris water maze using 9 animals in each group as in Example 1. The location of the platform was memorized by training. The bottom of the pool was divided into four lines with white lines, and a platform was placed in the center of one of these. Rats that remembered the platform location were exposed to oxidative stress (48 hours under 100% oxygen). Next, it was allowed to swim for 60 seconds in the water maze where the platform was removed, and the residence time of the section where the platform was located was measured during 4 fractions, and the memory retention rate was calculated by the following formula.
  • Memory retention (%) (average residence time for 9 days after exposure to oxidative stress / average residence time immediately before exposure to oxidative stress) X 100
  • FIG. 1 is a graph showing the effect on the speed of improvement of memory / learning ability shown in Example 1.
  • FIG. 2 is a graph showing the effect on memory retention shown in Example 2.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Food Science & Technology (AREA)
  • Nutrition Science (AREA)
  • Polymers & Plastics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Mycology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The purpose is to provide a brain function-improving agent having an effect of improving the leaning/memory ability and a functional food containing the brain function-improving agent. Disclosed is a preparation comprising both of pyrroloquinoline quinone or a salt thereof and coenzyme Q10. Also disclosed is a functional food containing the preparation. By using the preparation or the functional food, it becomes possible to improve the reduction in leaning/memory ability induced by a brain function disorder caused by various factors.

Description

脳機能改善剤及び該改善剤を含有する機能性食品  Brain function improving agent and functional food containing the improving agent
技術分野  Technical field
[0001] 本発明は、少なくとも、一般式（1)で示されるピロ口キノリンキノン類又はその塩を有 効成分として含むことを特徴とする、脳機能改善剤及び該改善剤を含有する機能性 食品に関する。また、本発明は、一般式（1)で示されるピロ口キノリンキノン類又はそ の塩と共にコェンザィム Q10を有効成分として含む脳機能改善剤及び該改善剤を 含有する機能性食品に関する。カゝかる脳機能改善剤及び機能性食品は、学習-記 憶能の低下改善効果を有するので、血管性或いは器質性の障害原因によって引き 起こされる脳の機能低下を改善する上で大変有用である。  [0001] The present invention comprises at least a brain function ameliorating agent characterized by containing as an active ingredient a pyroguchi quinoline quinone compound or a salt thereof represented by the general formula (1), and a functionality containing the improving agent. Regarding food. The present invention also relates to a brain function improving agent containing coenzyme Q10 as an active ingredient together with the pyroguchi quinoline quinones or salts thereof represented by the general formula (1) and a functional food containing the improving agent. The brain function improving agents and functional foods that are profitable have the effect of improving the learning-memory ability, and are therefore very useful in improving the brain function deterioration caused by the cause of vascular or organic disorders. is there.
[化 1]  [Chemical 1]
Figure imgf000003_0001
Figure imgf000003_0001
(但し、 R , R , Rは同一又は異なって、水素原子、アルキル基、ァルケ-ル基、ベ (However, R 1, R 2, and R are the same or different and represent a hydrogen atom, an alkyl group, an alkyl group,
1 2 3 one two Three
ンジル基、プロパギル基又はアルコキシカルボ-ルアルキル基を示す。）  An benzyl group, a propargyl group or an alkoxycarboalkyl group. )
背景技術  Background art
[0002] 近年、総人口に占める老人割合が急激に増加しており、それに伴って、加齢に伴う 学習、記憶能力の低下や、更には疾病としての痴呆症の増加が問題になっている。 痴呆症の原因疾患としては、アルツハイマー病に代表される脳変性疾患、脳梗塞や 脳出血等による脳血管障害、脳腫瘍、頭部外傷、感染症、代謝性疾患等が挙げられ る。特に、高齢ィ匕の進展に伴って患者数が著しく増加しているのはアルッノヽイマ一病 である。アルツハイマー病は日本では痴呆患者の約 30%、米国では 40〜60%を占 めると言われ、急激な短期の記銘カ '記憶力の低下、人格障害等を引き起こすことを 特徴としており、医療費、介護の面カゝら大きな社会問題になっている。  [0002] In recent years, the proportion of elderly people in the total population has increased rapidly, and accompanying this, there has been a problem of decline in learning and memory abilities associated with aging, as well as an increase in dementia as a disease. . Examples of the disease causing dementia include cerebral degenerative diseases such as Alzheimer's disease, cerebrovascular disorders caused by cerebral infarction and cerebral hemorrhage, brain tumors, head trauma, infectious diseases, metabolic diseases, and the like. In particular, the number of patients has increased significantly with the advancement of age. Alzheimer's disease is said to account for about 30% of dementia patients in Japan and 40-60% in the United States.It is characterized by a sudden short-term memory loss and personality disorder. Costs and nursing care have become major social issues.
本病では、脳組織の萎縮や脱落などを伴い、神経伝達物質であるアセチルコリン の減少が起こる。また、本病に特徴的なものとして、大脳皮質や海馬に存在する老人 斑、神経原繊維変化があり、老人斑の中心に存在するアミロイド ι8蛋白質と神経原繊 維変化の構成蛋白質であるタウ蛋白質の両面力 発病機構の研究が進められてい る。これらの発病機構を基に、治療薬の開発も進められており、アセチルコリンエステ ラーゼ阻害薬等が開発されて 、るが、十分な効果を上げて 、るとは未だ言 、難!/、。 即ち、発病後の回復は通常困難であり、対症療法的に進行を遅らせる治療にならざ るを得な 、のが現状である。 In this disease, acetylcholine, a neurotransmitter, is accompanied by atrophy and loss of brain tissue. Decrease occurs. Also characteristic of this disease are senile plaques and neurofibrillary tangles present in the cerebral cortex and hippocampus, and amyloid ι8 protein present in the center of senile plaques and tau, a component protein of neurofibrillary tangles. Research on the mechanism of pathogenesis of proteins is underway. Based on these pathogenic mechanisms, the development of therapeutic drugs is also progressing, and acetylcholinesterase inhibitors and the like have been developed. However, it is still difficult to say that they are effective enough! In other words, recovery after the onset of disease is usually difficult, and the current situation is that it must be treated symptomatically to slow the progression.
一方、近年、食品成分の機能研究が進み、脳機能に影響を与える成分も見出され ており、本病を予防し、かつ進行を抑える機能を食品に求める動きが活発になってい る（例えば、特許文献 1〜3参照)。これまで、脳の機能を賦活化する食品素材として ドコサへキサェン酸 (DHA)、イチヨウ葉エキス等が知られている力 それらの効果は 十分とはいえず、更に有効な食品素材の開発が切望されている。  On the other hand, in recent years, research on the function of food ingredients has progressed, and ingredients that affect brain function have also been found, and there is an active movement for foods to have functions that prevent this disease and suppress progression (for example, And Patent Documents 1 to 3). To date, docosahexaenoic acid (DHA), yew leaf extract, etc. are known as food materials that activate brain functions. Their effects are not sufficient, and the development of more effective food materials is eagerly desired. Has been.
[0003] 特許文献 1 :特開平 7— 17855号公報 Patent Document 1: Japanese Patent Laid-Open No. 7-17855
特許文献 2 :特開平 7— 143862号公報  Patent Document 2: JP-A-7-143862
特許文献 3 :特許第 3195594号公報  Patent Document 3: Japanese Patent No. 3195594
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0004] 本発明の目的は、血管性又は非血管性の原因によって障害された脳機能の改善効 果を有する製剤及びそのような製剤を含有する機能性食品を提供することを目的と する。 [0004] An object of the present invention is to provide a preparation having an effect of improving brain function impaired by a vascular or non-vascular cause, and a functional food containing such a preparation.
課題を解決するための手段  Means for solving the problem
[0005] 本発明者らはピロ口キノリンキノン類又はその塩の生理活性に関し研究を重ねた結 果、経口的に投与することによって該化合物が実験動物の学習、記憶能を著しく改 善する効果を見出し、更には、コェンザィム Q10と共に用いることによって相乗効果 を示すことを見出し、本発明を完成させた。 [0005] As a result of repeated studies on the physiological activity of pyroguchi quinoline quinones or salts thereof, the present inventors have found that the compound significantly improves learning and memory ability of experimental animals by oral administration. Furthermore, the present invention has been completed by finding that it can be used together with Coenzyme Q10 to show a synergistic effect.
即ち、本発明は、以下の 1〜4に示す、ピロ口キノリンキノン類又はその塩、及び所 望によりコェンザィム Q10を含有することを特徴とする、学習'記憶能低下改善等の 脳機能改善効果を有する製剤及び機能性食品に関するものであり、具体的には老 化及びアルツハイマー病等の痴呆症による学習 ·記憶能の低下を改善する脳機能 改善剤及び該改善剤を含有する機能性食品に関するものである。 That is, the present invention comprises a brain-opened quinoline quinone or a salt thereof shown in the following 1 to 4 and a coenzyme Q10 as desired, and the brain function improving effect such as improvement of learning and memory ability reduction Specific to pharmaceuticals and functional foods that have The present invention relates to a brain function improving agent that improves a decrease in learning and memory ability due to dementia such as Alzheimer's disease and Alzheimer's disease, and a functional food containing the improving agent.
1.一般式（1)で示されるピロ口キノリンキノン類又はその塩を少なくとも含むことを特 徴とする、脳機能改善剤。  1. A brain function improving agent characterized by comprising at least a pyroguchi quinoline quinone or a salt thereof represented by the general formula (1).
[化 2]  [Chemical 2]
RR
Figure imgf000005_0001
Figure imgf000005_0001
(但し、 R , R , Rは同一又は異なって、水素原子、アルキル基、ァルケ-ル基、ベ (However, R 1, R 2, and R are the same or different and represent a hydrogen atom, an alkyl group, an alkyl group,
1 2 3 one two Three
ンジル基、プロパギル基又はアルコキシカルボ-ルアルキル基を示す。 )  An benzyl group, a propargyl group or an alkoxycarboalkyl group. )
2.さらに、コェンザィム Q 10を含有する、上記 1項に記載の脳機能改善剤。  2. The brain function improving agent according to 1 above, further comprising Coenzyme Q10.
3.学習'記憶能低下改善用の、上記 1又は 2項に記載の脳機能改善剤  3. The brain function improving agent according to 1 or 2 above, which is used to improve learning and memory ability.
4.上記 1から 3項の何れか 1項に記載の脳機能改善剤を含有する機能性食品。 発明の効果  4. A functional food containing the brain function improving agent according to any one of 1 to 3 above. The invention's effect
[0006] 本発明は、ピロ口キノリンキノン類又はその塩、或いはピロ口キノリンキノン類又はそ の塩とコェンザィム Q10を有効成分として含む、学習'記憶能低下改善等の脳機能 改善効果を有する、脳機能改善剤及び該機能改善剤を含有する機能性食品に関す るものであり、具体的には老化及びアルツハイマー病等の痴呆症による学習 ·記憶能 の低下を改善する脳機能改善剤及び該改善剤を含有させた機能性食品に関するも のである。  [0006] The present invention comprises a pyroguchi quinoline quinone or a salt thereof, or a pyro mouth quinoline quinone or a salt thereof and coenzyme Q10 as active ingredients, and has an effect of improving brain function such as learning 'improvement of decreased memory ability, The present invention relates to a brain function improving agent and a functional food containing the function improving agent. Specifically, the brain function improving agent for improving deterioration of learning / memory ability due to aging and dementia such as Alzheimer's disease and the like It relates to functional foods containing improvers.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0007] 本発明は、ピロ口キノリンキノン類又はその塩、或いはピロ口キノリンキノン類又はそ の塩とコェンザィム Q10を有効成分として含む脳機能改善剤及び該改善剤を含有 する機能性食品に関する。 [0007] The present invention relates to a brain function-improving agent containing pyroguchi quinoline quinones or a salt thereof, or pyro mouth quinoline quinones or a salt thereof and Coenzyme Q10 as active ingredients, and a functional food containing the improving agent.
ピロ口キノリンキノンは、 1979年メタノール資化性菌のメタノール脱水酵素の補酵素 として見出され、細菌類以外にも、大豆、ソラ豆、ピーマン、ジャガイモ、パセリ、ホウ レンソゥ等の食用植物、又は酢、茶、ココア、納豆、豆腐等の加工食品からも検出さ れている。 Pillow mouth quinoline quinone was found in 1979 as a coenzyme for methanol-dehydrating enzymes of methanol-utilizing bacteria. In addition to bacteria, soybeans, soya beans, peppers, potatoes, parsley, potatoes It has also been detected in edible plants such as lotus roots and processed foods such as vinegar, tea, cocoa, natto and tofu.
ピロ口キノリンキノン類又はその塩は、有機化学的合成法 (例えば、 JACS、第 103卷 、 5599〜5600頁 (1981))及び発酵法 (例えば、特開平 1-218597号公報)などにより製造 することが可能である。  Pyromouth quinoline quinones or salts thereof are produced by organic chemical synthesis methods (for example, JACS, No. 103, pages 5599-5600 (1981)) and fermentation methods (for example, JP-A No. 1-218597). It is possible.
ピロ口キノリンキノン類又はその塩としては、一般式（1)で示されるピロ口キノリン類 又はその塩、例えばナトリウム塩、カリウム塩等のアルカリ金属の塩、マグネシウム塩、 カルシウム塩等のアルカリ土類の塩を例示することができるが、これらに限定されるも のではない。  As the pyroguchi quinoline quinones or salts thereof, pyroguchi quinolines represented by the general formula (1) or salts thereof, alkaline metal salts such as sodium salts and potassium salts, alkaline earths such as magnesium salts and calcium salts However, the salt is not limited to these.
[0008] 従来、ピロ口キノリンキノン類又はその塩は医薬品を目的として、静注又は腹腔内投 与で評価されてきたが、これら経路での投与は実用的ではなぐ侵襲的であると共に 副作用が出やすいと言う大きな問題があった。このため、副作用を伴うことなく効果を 発揮させることができず、有効性の評価も的確になされていなかつたが、本発明者ら は、意外にも、経口的に摂取させることにより、該化合物は極めて低摂取量で学習 · 記憶能低下改善等の脳機能改善効果を示し、しかも、その有効摂取量の範囲が極 めて広ぐ高摂取量でも副作用が出現しないことを見出した。これらのことは、ピロロキ ノリンキノン類又はその塩が、安全な機能性食品素材として使用可能であることを示 している。  [0008] Conventionally, pyro-quinoline quinones or salts thereof have been evaluated by intravenous injection or intraperitoneal injection for the purpose of pharmaceuticals, but administration by these routes is not practical and has side effects. There was a big problem that it was easy to come out. For this reason, the effect could not be exerted without causing side effects, and the effectiveness was not accurately evaluated, but the present inventors unexpectedly took the compound by taking it orally. We found that brain intake was effective at improving brain function such as learning and memory ability improvement at extremely low intakes, and that no side effects appeared even at high intakes where the range of effective intake was extremely wide. These facts indicate that pyrroloquinoline quinones or salts thereof can be used as a safe functional food material.
[0009] 一般式（1)で示されるピロ口キノリンキノン類又はその塩は、単独或いはコェンザィ ム Q10と組み合わせて使用するが、更に他の機能性食品素材と組み合わせても使 用できる。組み合わせ可能な機能性食品素材としては、 L—カル-チン、 a—リポ酸 、ビタミン B群、ビタミン C、ビタミン E等の食品として用いられているビタミン類、ァミノ 酸類、ァスタキサンチン、 a—カロテン、 /3—カロテン等のカロテノイド、ドコサへキサ ェン酸、エイコサペンタエン酸等の ω 3脂肪酸、ァラキドン酸等の ω 6脂肪酸等が例 示される力 これらに限定されるものではない。 [0009] The pyroguchi quinoline quinones or salts thereof represented by the general formula (1) are used alone or in combination with Coenzyme Q10, but can also be used in combination with other functional food materials. Functional food materials that can be combined include L-carcin, a- lipoic acid, vitamin B group, vitamin C, vitamin E, vitamins used as food, amino acids, austaxanthin, a — Carotenoids, carotenoids such as / 3-carotene, omega 3 fatty acids such as docosahexaenoic acid and eicosapentaenoic acid, omega 6 fatty acids such as arachidonic acid, etc. are not limited to these.
また、本発明の一般式（1)で示されるピロ口キノリンキノン類又はその塩、或いは、こ れとコェンザィム Q10を共に含む脳機能改善剤は、飲食物の形態、即ち、ドリンク、 シロップ、各種病院食、栄養補強食、 日常食する飲食物の形態でも、錠剤、カプセル 剤、顆粒剤の形態でも使用可能である。調製の際使用される添加剤としては、液剤と しては水、果糖、ブドウ糖等の糖類、落下生油、大豆油、ォリーブ油等の油類、ポリエ チレングリコール、ポリプロピレングリコール等のグリコール類を用いることができる。 錠剤、カプセル剤、顆粒剤などの固形剤の賦型剤としては乳糖、ショ糖、マンニット、 滑沢剤としてはカオリン、タルク、ステアリン酸マグネシウム、崩壊剤としてデンプン、 アルギン酸ナトリウム、結合剤としてポリビュルアルコール、セルロース、ゼラチン、界 面活性剤としては脂肪酸エステル類、可塑剤としてグリセリン等を例示することができ るが、これらに限定されるものではない。 In addition, the cerebral quinoline quinones or salts thereof represented by the general formula (1) of the present invention or a brain function improving agent containing both of them and Coenzyme Q10 are in the form of food and drink, that is, drinks, syrups, various kinds. Even in the form of hospital food, nutrition-enhanced food, food and drink to eat everyday, tablets and capsules It can also be used in the form of agents and granules. Additives used in the preparation include saccharides such as water, fructose and glucose, oils such as falling raw oil, soybean oil and olive oil, and glycols such as polyethylene glycol and polypropylene glycol. Can be used. Lactose, sucrose, mannitol as excipients for solid preparations such as tablets, capsules, granules, etc., kaolin, talc, magnesium stearate as lubricants, starch, sodium alginate as disintegrants, poly as binder Examples of the butyl alcohol, cellulose, gelatin, and surfactant include fatty acid esters, and examples of the plasticizer include glycerin, but are not limited thereto.
実施例  Example
[0010] 以下、実施例を挙げて本発明を具体的に説明するが、本発明はこれらの例によつ て限定されるものではない。  Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.
[0011] ¾細  [0011] ¾fine
雄ウィスター系ラット (9週齢)を、ピロ口キノリンキノンニナトリウム塩 (PQQ '2Na) 0.02% 若しくはコェンザィム QlO(CoQ10)0.3%を、両者併せて又は単独に添加した飼料、或 いは何れも含まない無添加飼料で飼育し、飼育 21日後の 12週齢から、各群 9匹を用 いてモーリス水迷路による学習 ·記憶能力に関する試験を行った。即ち、円形のブー ル (直径 150cm、深さ 45cm)の底を白線で 4分割し、そのうちの 1分画の中央部に、水中 に隠れるように円形のプラットホームを置き、各ラットをプラットホームのない他の分画 3力所の異なった位置力 遊泳させ、プラットホーム上に止まるまでの時間を測定した 。本試験は毎日 1試行、計 20日間行った。学習率は以下の式により算出した。  Male Wistar rats (9-week-old) were fed either or both with or without quinoline quinoline disodium salt (PQQ '2Na) 0.02% or Coenzyme QlO (CoQ10) 0.3%. The animals were reared with no added feed, and from 12 weeks of age 21 days after the rearing, tests were conducted on learning and memory ability using the Morris water maze using 9 animals in each group. In other words, the bottom of a circular boule (diameter 150 cm, depth 45 cm) is divided into four parts by white lines, and a circular platform is placed in the center of one of the fractions so as to be hidden underwater, and each rat has no platform. Different fractional forces at the other three fractions were measured by swimming and resting on the platform. This study was conducted on a trial basis for 20 days. The learning rate was calculated by the following formula.
学習率 (%) = 100— (X回目の到達時間の平均 /1回目の到達時間の平均) X 100 上記水迷路試験において、回数を重ねる毎に PQQ '2Na添加群、無添加群とも学 習率は上昇していくが、 PQQ '2Na添加群で統計的に有意に上昇速度が速ぐ PQQ - 2Naが記憶 ·学習能力を高めることが確認された。結果を図 1に示す。  Learning rate (%) = 100— (Average time for X times / average time for first times) X 100 In the above water maze test, learning is performed for both the PQQ '2Na addition group and the non-addition group each time the number of times is repeated. Although the rate increases, it is confirmed that PQQ-2Na increases memory and learning ability, which is statistically significantly faster in the PQQ '2Na addition group. The results are shown in Figure 1.
[0012] 施例 2 [0012] Example 2
雄ウィスター系ラット (9週齢)を用い、 PQQ '2Na0.02%若しくは CoQIO 0.3%を、両者 併せて又は単独に添加した飼料、或いは何れも含まない無添加飼料で飼育し、飼育 21日後の 12週齢から、実施例 1と同様に各群 9匹を用いて、モーリス水迷路を使用し た訓練によりプラットホームの位置を記憶させた。なお、プールの底は白線で 4分画し 、そのうちの 1分画の中央部にプラットホームを置いた。プラットホームの位置を記憶し たラットを酸化ストレス (100%酸素下に 48時間)に曝した。次に、プラットホームを取り除 いた水迷路に 60秒間遊泳させ、 4分画中、プラットホームがあった区画の滞留時間を 測定し、以下の式により記憶保持率を算出した。 Male Wistar rats (9 weeks old) were used to feed PQQ '2Na 0.02% or CoQIO 0.3%, both in combination or singly, or in an additive-free diet. From the age of 12 weeks, using the Morris water maze using 9 animals in each group as in Example 1. The location of the platform was memorized by training. The bottom of the pool was divided into four lines with white lines, and a platform was placed in the center of one of these. Rats that remembered the platform location were exposed to oxidative stress (48 hours under 100% oxygen). Next, it was allowed to swim for 60 seconds in the water maze where the platform was removed, and the residence time of the section where the platform was located was measured during 4 fractions, and the memory retention rate was calculated by the following formula.
記憶保持率 (%) = (酸化ストレス曝露後の 9日間の平均滞留時間/酸化ストレス曝露直 前の平均滞留時間) X 100 Memory retention (%) = (average residence time for 9 days after exposure to oxidative stress / average residence time immediately before exposure to oxidative stress) X 100
その結果を図 2に示す。記憶保持率の平均値は PQQ '2Na及び CoQIO添加群で最 も高ぐ PQQ '2Na単独添加群がこれに次いだ。また記憶保持率の平均値には、 PQQ • 2Naと CoQ 10にお!/、て有意な相乗効果が認められた。  The results are shown in Fig. 2. The average value of memory retention was highest in the PQQ '2Na and CoQIO addition groups, followed by the PQQ' 2Na alone addition group. In addition, a significant synergistic effect was observed for PQQ • 2Na and CoQ 10 in the average memory retention rate!
図面の簡単な説明 Brief Description of Drawings
[図 1]実施例 1に示した記憶 ·学習能力の向上速度に及ぼす効果を表したグラフであ る。 FIG. 1 is a graph showing the effect on the speed of improvement of memory / learning ability shown in Example 1.
[図 2]実施例 2に示した記憶保持力に及ぼす効果を表したグラフである。  FIG. 2 is a graph showing the effect on memory retention shown in Example 2.

Claims

請求の範囲 The scope of the claims
一般式（1)で示されるピロ口キノリンキノン類又はその塩を少なくとも含むことを特徴 とする、脳機能改善剤。  A brain function improving agent characterized by comprising at least a pyroguchi quinoline quinone represented by the general formula (1) or a salt thereof.
Figure imgf000009_0001
Figure imgf000009_0001
(但し、 R , R , Rは同一又は異なって、水素原子、アルキル基、ァルケ-ル基、ベ (However, R 1, R 2, and R are the same or different and represent a hydrogen atom, an alkyl group, an alkyl group,
1 2 3 one two Three
ンジル基、プロパギル基又はアルコキシカルボ-ルアルキル基を示す。 )  An benzyl group, a propargyl group or an alkoxycarboalkyl group. )
[2] さらに、コェンザィム Q 10を含有する、請求項 1に記載の脳機能改善剤。  [2] The brain function improving agent according to claim 1, further comprising Coenzyme Q10.
[3] 学習'記憶能低下改善用の、請求項 1又は 2に記載の脳機能改善剤  [3] The brain function-improving agent according to claim 1 or 2, which is used for improvement of learning and memory ability decline.
[4] 請求項 1から 3の何れか 1項に記載の脳機能改善剤を含有する機能性食品。  [4] A functional food containing the brain function improving agent according to any one of claims 1 to 3.
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JPWO2007119588A1 (en) 2009-08-27
EP2011498A1 (en) 2009-01-07
CN101443010A (en) 2009-05-27
US20090192312A1 (en) 2009-07-30

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